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Phenotype switching: plasticity and/or differentiation of stromal cells and their progenitors within the tumour microenvironment regulate tumour fate.

Periodic Reporting for period 3 - PhenoSwitch (Phenotype switching: plasticity and/or differentiation of stromal cells and their progenitors within the tumour microenvironment regulate tumour fate.)

Reporting period: 2021-04-01 to 2022-09-30

The limited success of cancer therapy especially in advanced metastatic disease warrants a reassessment. Of particular interest is our basic understanding of the nature of cancer cells and the factors that allow them to proliferate and metastasise. Fibroblasts, endothelial, immune, adipose and mesenchymal cells make up the majority of stromal cells. These stromal cells significantly affect cancer cell characteristics and tumour fate. Here, we propose to elucidate the role of stromal cells and a small population of non-committed stem or progenitor cells, which we term “cancer stromal stem cells” CSSCs in tumour growth and metastases. We hypothesise that such cells reside in the tumour niche and have the potential to differentiate into tumour-promoting cells in response to environmental factors. Cancer cells trigger the differentiation of CSSCs into specific stromal cell types, thereby inducing a phenotypic and functional switch that skews them towards a tumour-promoting phenotype hence promoting tumor cell aggressiveness and metastases. To test our hypothesis, we will use high-throughput technologies to track the lineage, differentiation and commitment of CSSCs during tumour progression.
When studying this research path, we will be able to identify new ways to block the tumour-promoting phenotypic switch and maintaining a tumour-restricting stromal microenvironment represent novel strategies in the fight against cancer. This study will lead to the development of new tools to predict prognosis and pharmacological strategies to restrict tumour growth.
The overall objectices are therefore:
(a) Systematically analyse tumour-promoting and tumour-restricting stromal phenotypes at the cellular and molecular levels.
(b) Characterise stromal cell plasticity and the contribution of tumour cells to the phenotype switch.
(c) Determine whether stromal cell and CSSC phenotype in cancer patients can predict clinical outcome.
(d) Screen for molecules that inhibit the tumour-promoting stromal switch.
The following actions and achievements were performed since ERC PhenoSwitch grant initiation, and that are within our activities tasks and time frame:
Aim 1: We systemically analyzed tumor promoting and tumor restricting stromal phenotype at the cellular level using met-high and met-low tumors. We established the system of met-low and met-high tumor pairs (breast and melanoma) and manage phenotypically to demonstrate hematopoietic stem cells (HSCs) in the tumor stroma, where we see more HSCs cells in met-high tumors compare to met-low tumors. This is verified by cholinergic and genetic approaches.
Aim 2: We characterize HSC cell placticity and their contribution to phenotype switch in tumors. Specifically, we managed to show how met-high tumors can “educate” HSCs to induce a pro-metastatic tumor microenvironment by secreting interleukin 6 (IL-6) which in turn programs the HSCs to differentiate into tumor-associated macrophages (TAMs), therefore supporting a metastatic switch in the tumor milieu. This was done by combining phenotype studies with advanced genetic approaches (single cell RNA-seq) and the analysis of protein expression patterns of tumor cells using advanced multi-omics techniques. Using this approach, we were able to reveal this unique crosstalk between tumor cells and HSCs, where met-high tumors secreting IL-6 dictate a specific genetic signature in HSCs that programs them towards myeloid differentiation, thereby inducing a metastatic switch.
Aim 3: We currently collect samples from cancer patients in order to identify HSCs in the tumor and blood circulation. The results are ongoing.
So far, our studies provide new insight into the mechanism by which tumors contribute to the phenotypic switch of supporting stroma. This study is with no delays and is actually progressed in a very satisfied manner, covering Aim 1, and parts of Aim 2 and 3. This study is in its final steps towards publication.
Many studies have attempted to identify and characterise specific cells in the tumour microenvironment that may contribute to tumour growth and metastasis. However, the approach we present here is unique and novel.
Here, we will focus on the role of “young” and “mature” stroma in regulating tumour fate:
1. The existence of CSSCs in early-stage tumours suggests that these naïve cells have still not acquired a tumour-promoting role. This has never been shown before, and we were able to identify HSC in the tumor.
2. The differentiation of CSSCs may correlate with the development of an aggressive tumour phenotype - this we have still need to analyze and identify whether the cells undergo differentiation.
3. Identifying factors which promote the commitment and maturation of CSSCs to tumour-supporting stromal cells - we identified one such factor, and we will identify additional factors in the future.
4. Searching for ways to inhibit the factors promoting cell differentation towards tumour-supporting stromal cells - this we still need to work on, as we have not identified many of such factors.
Overall, our study will allow a better characterisation of how “mature” the tumour is, and whether it can be “shaped” or “reprogrammed” into a non-aggressive tumour.
the overall phenoswitch project